PXD011926

PXD011926 is an original dataset announced via ProteomeXchange.

Title	Lztr1 loss leads to Noonan syndrome-like vascular defects by dysregulating vesicular trafficking
Description	Mutations in LZTR1, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, are associated with glioma, hepatocarcinoma, paediatric cancers, Schwannomatosis, and Noonan syndrome (NS). NS is a poorly understood and complex disease. The variety of NS phenotypes makes it challenging to elucidate the molecular mechanisms by which mutations in LZTR1 drive human disease. Using an Lztr1 knockout model, we assessed the effect of Lztr1 loss on endothelial function. Moreover, the molecular alterations mediated by Lztr1 loss were evaluated by mass-spectrometry (MS)-based ubiquitome and proteome analysis. These analyses demonstrated that Lztr1 loss affects vesicular trafficking. We identified the ESCRT III member CHMP1B as a substrate for the LZTR1/CUL3 ubiquitin complex and could show that disease-related LZTR1 mutations abolish the interaction with CHMP1B. LZTR1-mediated ubiquitination of CHMP1B facilitates its interaction with IST1 that affects the dynamics of fusion and fission of endosomal vesicles. Dysregulation of vesicular trafficking triggered by Lztr1 loss leads to up-regulation of VEGF signaling due to endosomal accumulation and activation of VEGFR2. This novel molecular mechanism provides a fundamental explanation for the role of LZTR1 in endothelial function and justify the use of anti-VEGF therapies for the treatment of NS patients.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:13:26.275.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Impens Francis
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	ubiquitinylated lysine; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF; LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2018-12-03 08:27:16	ID requested
1	2020-10-13 22:59:52	announced
⏵ 2	2024-10-22 05:13:27	announced	2024-10-22: Updated project metadata.

10.1161/circresaha.119.315730;

Sewduth RN, Pandolfi S, Steklov M, Sheryazdanova A, Zhao P, Criem N, Baietti MF, Lechat B, Quarck R, Impens F, Sablina AA, Controls Cardiovascular Function by Regulating Vesicular Trafficking. Circ Res, 126(10):1379-1393(2020) [pubmed]

curator keyword: Biomedical

submitter keyword: HeLa cells, VEGF,Noonan syndrome, Lztr1, vesicular trafficking, ubiquitin, CHMP1B

Anna A Sablina
contact affiliation	VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium Department of Oncology, KU Leuven, Herestraat 49, Leuven, Belgium
contact email	anna.sablina@kuleuven.vib.be
lab head
Impens Francis
contact affiliation	VIB Proteomics Core Ghent University
contact email	francis.impens@vib-ugent.be
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/10/PXD011926

PRIDE project URI

• PRIDE
  1. PXD011926
     1. Label: PRIDE project
     2. Name: Lztr1 loss leads to Noonan syndrome-like vascular defects by dysregulating vesicular trafficking